The unfolded protein response (UPR) is an intracellular signaling pathway which responds to the accumulation of misfolded proteins in the endoplasmic reticulum (ER) lumen. The UPR is increasingly recognized as a significant factor in many human diseases. Up-regulation of the UPR is thought to be important for tumor survival and B-cell autoimmunity, whereas UPR suppression is implicated in diseases such as Alzheimer's disease and type II diabetes.
IRE-1α is a transmembrane signaling molecule with an N-terminal luminal domain inside the ER and a C-terminal kinase and RNase domain in the cytosol. The N-terminal luminal domain complexes with GRP78. IRE-1α is an ER stress sensor. When activated, IRE-1α induces transcription of endoplasmic reticulum stress response genes, such as GRP78 and GRP94, by activating the transcription factor XBP-1 via specific RNA splicing.
Antagonists of IRE-1α are useful for treating B-cell autoimmune diseases and cancer. Agonists of IRE-1α are useful for treating Alzheimer's disease and type II diabetes. It would, therefore, be useful to have methods of screening for IRE-1α agonist and antagonist molecules.